Hepatic fibrosis results from chronic liver injury induced by alcohol abuse, hepatitis and other causes that progresses to cirrhosis and liver dysfunction. The hormone relaxin has shown promise as an antifibrotic agent in a number of tissues, including the liver, and relaxin has antifibrotic effects on hepatic stellate cells, the major source of fibrillar collagen in liver disease. Little is known about the expression of relaxin receptors and their ligands during the progression of hepatic fibrosis. The objective is to define the contribution of relaxin family hormones to the pathogenesis and treatment of fibrotic liver disease by testing the hypothesis that interaction of relaxin ligands with specific receptors contributes to protection against hepatic fibrosis. To test this hypothesis, three specific aims are proposed: Specific Aim #1. Determine the therapeutic efficacy of using relaxin peptide hormones alone and in combination to treat experimental liver disease. Specific Aim #2. Determine the role of relaxin receptors in the progression and resolution of experimental liver disease using relaxin receptor-null mice. Specific Aim #3. Define the relationship between relaxin receptor signaling and the antifibrotic action of peroxisome proliferator-activated receptor gamma. To achieve these aims, relaxin peptides alone and in combination will be used to treat experimental liver disease. Relaxin receptors-null mice will be used in models of liver disease to directly determine the role of the relaxin receptors in the progression of and recovery from of liver disease. The relaxin signaling through the cAMP/protein kinase A and peroxisome proliferator-activated receptor gamma (PPARy) pathways will be defined, and the combined effect of relaxin peptides and PPARy agonists on treatment of experimental hepatic fibrosis will be determined. The proposed research is significant, because understanding the response to treatment with relaxin receptor ligands, the role of the relaxin receptors in liver disease progression and resolution, and the signaling pathways regulated by relaxin receptors, will allow the development of new strategies to treat hepatic fibrosis. Cirrhosis affects 900,000 people and causes 36,000 deaths in the US annually. Treatment is currently limited to removal of the cause of the injury, which is not always possible or effective, or transplantation. The research proposed in this application may lead to targeted therapeutic strategies for the treatment of liver disease, a major health concern in the United States.